Discovery Proteomics and Nonparametric Modeling Pipeline in the Development of a Candidate Biomarker Panel for Dengue Hemorrhagic Fever

Brasier, Allan R.; Garcia, Josefina; Wiktorowicz, John E.; Spratt, Heidi; Comach, Guillermo; Ju, Huangxian; Recinos, Adrián; Soman, Kizhake V.; Forshey, Brett M.; Halsey, Eric S.; Blair, Patrick J.; Rocha, Claudio; Bazán, Isabel; Victor, Sundar; Wu, Ziyan; Stafford, Susan; Watts, Douglas M.; Morrison, Amy C.; Scott, Thomas W.; Kochel, Tadeusz J.

doi:10.1111/j.1752-8062.2011.00377.x

Cited by 34 publications

(43 citation statements)

References 45 publications

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“…The BAP pre-separation fractionation system is a semi-automated device to fractionate plasma into protein and peptide pools (12). The protein pools were depleted of the most highly abundant proteins and labeled with BODIPY FL-maleimide (BD) (27, 28).…”

Section: Methodsmentioning

confidence: 99%

“…Risk factors for complicated DENV infections are multifactorial; these include host genetic factors (5-10), viral strains (11-13), anamnestic immune response from previous heterologous exposure (14-16), age (17, 18) and/or gender effects (12). Not surprisingly, then, the clinical manifestations of DENV infection is highly variable in terms of times of onset, involvement of thrombocytopenia (19, 20), manifestations of endothelial injury/vascular leak (21), myositis, arthralgias and hepatic involvement (22, 23).…”

Section: Background and Objectivesmentioning

confidence: 99%

“…As a result, the World Health Organization (WHO) refined dengue case classification schemes in 2009 to include the identification of non-severe dengue with early warning signs (24). Accordingly, approaches seeking to discriminate acute, self-limited infections vs those that will progress to SDD have yielded inconsistent results (12, 22, 23, 25). …”

Section: Background and Objectivesmentioning

confidence: 99%

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Molecular classification of outcomes from dengue virus -3 infections

Brasier¹,

Zhao²,

Wiktorowicz³

et al. 2015

Journal of Clinical Virology

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Objectives Dengue virus (DENV) infection is a significant risk to over a third of the human population that causes a wide spectrum of illness, ranging from sub-clinical disease to intermediate syndrome of vascular complications called Dengue Fever Complicated (DFC) and severe, dengue hemorrhagic fever (DHF). Methods for discriminating outcomes will impact clinical trials and understanding disease pathophysiology. Study Design We integrated a proteomics discovery pipeline with a heuristics to develop a molecular classifier to identify an intermediate phenotype of DENV-3 infectious outcome. Results 121 differentially expressed proteins were identified in plasma from DHF vs dengue fever (DF), and informative candidates were selected using nonparametric statistics. These were combined with markers that measure complement activation, acute phase response, cellular leak, granulocyte differentiation and viral load. From this, we applied quantitative proteomics to select a 15 member panel of proteins that accurately predicted DF, DHF, and DFC using a Random Forest Classifier. The classifier primarily relied on acute phase (A2M), complement (CFD), platelet counts and cellular leak (TPM4) to produce an 86% accuracy of prediction with an area under the receiver operating curve of >0.9 for DHF and DFC vs DF. Conclusions Integrating discovery and heuristic approaches to sample distinct pathophysiological processes is a powerful approach in infectious disease. Early detection of intermediate outcomes of DENV-3 will speed clinical trials evaluating vaccines or drug interventions.

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Section: Methodsmentioning

confidence: 99%

Section: Background and Objectivesmentioning

confidence: 99%

Section: Background and Objectivesmentioning

confidence: 99%

See 1 more Smart Citation

Molecular classification of outcomes from dengue virus -3 infections

Brasier¹,

Zhao²,

Wiktorowicz³

et al. 2015

Journal of Clinical Virology

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“…Advances in MS and protein identification have made possible identification and quantification of levels of cellular proteins in response to dengue virus infection [94]. Previously, the differential protein expression in serum samples from dengue-infected patients resulted in the identification of cellular proteins with potential to become targets in dengue pathogenesis [95,96]. Sensitivity and resolution are issues that have been solved with modern proteomic techniques, specifically MS detection.…”

Section: Future Perspectivementioning

confidence: 99%

Dengue Laboratory Diagnosis: Still Some Room for Improvement

et al. 2015

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Dengue is the most important and widely distributed arthropod-borne viral disease affecting humans. The number of dengue virus infections has steadily grown and more than 100 countries survey dengue incidence every year. Due to the lack of an approved antiviral treatment or licensed preventative vaccine, accurate and opportune diagnosis is commended for efficient dengue epidemiological surveillance, to propose control measures in order to curtail outbreaks timely and treat patients satisfactorily. In this review, the basis, application and indications for different diagnostic tests are described, and their advantages and limitations considered. At the end of this piece, we speculate what the future may hold for the diagnosis of dengue infections. KeywordsThe four serotypes of dengue virus (DENV 1-4) may equally be the cause of dengue infection in humans. DENV is a member of the Flaviviridae family, genus Flavivirus and is transmitted by the bite of female mosquitoes of the Aedes genus, mainly Aedes aegypti; an anthropophilic arthropod extensively distributed [1,2]. The viral genome is constituted by a single RNA strand of positive polarity of approximately 11 kb. It encodes three structural proteins: the envelope (E), pre-membrane/membrane (prM/M) and capsid (C) proteins; and seven nonstructural (NS) proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5), which are implicated in viral translation, replication and modulation of the host immune response [2,3]. Dengue prevails in 128 countries and it is estimated that more than 2.5 billion people (two fifths of the world's population) are at risk of DENV infection [1,2]. Every year over 50 million DENV infections occur, causing more than 500,000 severe cases of dengue and resulting in at least 125,000 fatalities. The enormous increase in dengue prevalence observed in the last decades is multifactorial in nature. Unplanned and uncontrolled urbanization caused by the global population growth is associated with the deterioration in water supply quality and poor sewer and waste management systems availability. These conditions are ideal for the domestic propagation of the vector and a hallmark for the most recent epidemic outbreaks observed in tropical regions of the world such as Southeast Asia and South America. In addition, the modern trade globalization facilitates the introduction of the vector and all DENV serotypes to previously uninfected populated centers [1,4,5], where a highly dense susceptible population may be at risk. In this way, over the last decades DENV infection has become a global menace not only for tropical regions of the world, where the vector thrives, but also for temperate zones starting to be colonized by Aedes mosquitoes. The annual cost of dengue disease is estimated at US$135 million in Asiatic countries alone [6].

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“…3 Previously identified markers of dengue severity include cytokines (i.e., tumor necrosis factor alpha [TNFα] and Interleukin 6 [IL-6]), vascular permeability proteins, clotting cascade regulators, and gene expression profiles. [4][5][6][7][8][9][10][11][12][13][14][15][16][17] These severity markers are not, however, currently being used to guide patient management. 18,19 It is unclear why these severity markers are not being used, possibly because detection methods are expensive, slow, or require sophisticated equipment.…”

Section: Introductionmentioning

confidence: 99%

Discovery and Characterization of Potential Prognostic Biomarkers for Dengue Hemorrhagic Fever

Poole-Smith

Gilbert

Gonzalez

et al. 2014

The American Journal of Tropical Medicine and Hygiene

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Abstract. Half a million patients are hospitalized with severe dengue every year, many of whom would die without timely, appropriate clinical intervention. The majority of dengue cases are uncomplicated; however, 2-5% progress to severe dengue. Severe dengue cases have been reported with increasing frequency over the last 30 years. To discover biomarkers for severe dengue, we used surface-enhanced laser desorption/ionization time-of-flight mass spectrometry to analyze dengue virus positive serum samples from the acute phase of infection. Using this method, 16 proteins were identified as candidate biomarkers for severe dengue. From these 16 biomarkers, three candidates were selected for confirmation by enzyme-linked immunosorbent assay and Western blot: vitronectin (Vtn, 55.1 kDa), hemopexin (Hx, 52.4 kDa), and serotransferrin (Tf, 79.2 kDa). Vitronectin, Hx, and Tf best differentiated between dengue and severe dengue.

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Discovery Proteomics and Nonparametric Modeling Pipeline in the Development of a Candidate Biomarker Panel for Dengue Hemorrhagic Fever

Cited by 34 publications

References 45 publications

Molecular classification of outcomes from dengue virus -3 infections

Molecular classification of outcomes from dengue virus -3 infections

Dengue Laboratory Diagnosis: Still Some Room for Improvement

Discovery and Characterization of Potential Prognostic Biomarkers for Dengue Hemorrhagic Fever

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